Neuroscience and Biobehavioral Reviews 80 (2017) 286–305

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review article

Habituation is altered in neuropsychiatric disorders—A comprehensive T

review with recommendations for experimental design and analysis
⁎
Troy A. McDiarmida,c, Aram C. Bernardosa,c, Catharine H. Rankinb,c,
a
Graduate Program in Neuroscience, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada
b
Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, British Columbia, V6T 1Z4, Canada
c
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Rm F221, 2211 Wesbrook Mall, Vancouver, British Columbia, V6T 2B5, Canada

A R T I C L E I N F O A B S T R A C T

Keywords: Abnormalities in the simplest form of learning, habituation, have been reported in a variety of neuropsychiatric
Habituation disorders as etiologically diverse as Autism Spectrum Disorder, Fragile X syndrome, Schizophrenia, Parkinson’s
Neuropsychiatric disorders Disease, Huntington’s Disease, Attention Deficit Hyperactivity Disorder, Tourette’s Syndrome, and Migraine.
Disorders of Habituation Here we provide the first comprehensive review of what is known about alterations in this form of non-asso-
Autism Spectrum Disorder
ciative learning in each disorder. Across several disorders, abnormal habituation is predictive of symptom se-
Fragile X syndrome
verity, highlighting the clinical significance of habituation and its importance to normal cognitive function.
Schizophrenia
Parkinson’s disease Abnormal habituation is discussed within the greater framework of learning theory and how it may relate to
Huntington’s disease disease phenotype either as a cause, symptom, or therapy. Important considerations for the design and inter-
Attention Deficit Hyperactivity Disorder pretation of habituation experiments are outlined with the hope that these will aid both clinicians and basic
Tourette’s syndrome researchers investigating how this simple form of learning is altered in disease.
Migraine
Learning
Memory
Plasticity
Sensory processing
Adaptive filtering
Treatment

“Together, nonassociative learning and nonassociative gating constitute
an intelligent ‘firewall’ that constantly triages vast amounts of sensory
information into actionable and non-actionable categories in order to
prioritize. This firewall mechanism shields the mind from the vast
amounts of inundating sensory information that constantly compete with
one another for attention, and spares it the trouble of having to respond
to every tingling except the most salient ones. The triage process not only
helps to preserve mental sanity but also conserve physical energy, both of
which are important for survival.”
Poon and Young (2006)
1. Introduction
Although abnormal habituation has been observed in numerous
neurological and neuropsychiatric disorders a comprehensive review of
how this form of non-associative learning is altered in each disorder is
lacking. Habituation is a non-associative form of learning, defined as a
response decrement resulting from repeated stimulation that cannot be
explained by sensory adaptation or motor fatigue, and has conserved
behavioural characteristics present in all organisms studied (Table 1,
adapted from Rankin et al., 2009). In lay terms, habituation may be
described as the ability to “ignore the familiar, predictable, and in-
consequential,” a process almost ubiquitously presumed to be crucial
for normal cognitive function. For this reason, habituation is con-
ceptualized as a “building block of cognition,” essential to attention,
saliency mapping, and more complex forms of learning and memory.
This is supported by the observation that there is a correlation between
the rate of habituation in infancy and later IQ scores (Kavšek, 2004;
McCall and Carriger, 1993).
Despite its ubiquity and importance to normal cognitive function,
remarkably little is known about the cellular and molecular processes
underlying habituation (Giles and Rankin, 2009; Glanzman, 2009;
Ramaswami, 2014; Schmid et al., 2014; Wilson and Linster, 2008).
Indeed, several lines of evidence suggest that this elementary form of
plasticity is mediated by multiple mechanisms which are recruited by

⁎
Corresponding author.
E-mail address: crankin@psych.ubc.ca (C.H. Rankin).

http://dx.doi.org/10.1016/j.neubiorev.2017.05.028
Received 14 December 2016; Accepted 29 May 2017
Available online 01 June 2017
0149-7634/ © 2017 Elsevier Ltd. All rights reserved.
T.A. McDiarmid et al. Neuroscience and Biobehavioral Reviews 80 (2017) 286–305

Table 1 researchers investigating habituation and disease. Understanding the

The ten behavioural characteristics of habituation (Rankin et al., 2009). habituation deficits in one disorder may serve as a catalyst for studies of
another disorder. An additional goal of this review is to provide ex-
The Behavioural Characteristics of Habituation
perimental design and interpretation guidelines that will allow for more
1. Repeated application of a stimulus results in a progressive decrease in some consistent observations across studies. An accurate understanding of
parameter of a response to an asymptotic level. This change may include how habituation is altered in a disorder will facilitate the use of habi-
decreases in frequency and/or magnitude of the response. In many cases, the
tuation as a tool for differential diagnosis and will allow for more ac-
decrement is exponential, but it may also be linear; in addition, a response may
show facilitation prior to decrementing because of (or presumably derived from) curate animal models to investigate the cellular and molecular me-
a simultaneous process of sensitization. chanisms underlying these learning impairments.
2. If the stimulus is withheld after response decrement, the response recovers at least
partially over the observation time (“spontaneous recovery”). 2. Neuropsychiatric disorder inclusion criteria
3. After multiple series of stimulus repetitions and spontaneous recoveries, the
response decrement becomes successively more rapid and/or more pronounced
(“potentiation of habituation”). Not all neuropsychiatric disorders show abnormal habituation,
4. Other things being equal, more frequent stimulation results in more rapid and/or however a surprising number do. To generate a list of the most pre-
more pronounced response decrement, and more rapid spontaneous recovery (if valent neuropsychiatric conditions for which there is also a substantive
the decrement has reached asymptotic levels).
literature investigating habituation we queried PubMed for each of the
5. Within a stimulus modality, the less intense the stimulus, the more rapid and/or
more pronounced the behavioural response decrement. Very intense stimuli may disorder categories listed in DSM-V (American Psychiatric Association,
yield no significant observable response decrement. 2013) and the 12 disorders listed as the most common neurological
6. The effects of repeated stimulation may continue to accumulate even after the disorders according to Hirtz et al. (2007). Only disorders with more
response has reached an asymptotic level (which may or may not be zero, or no than five empirical research articles comparing habituation in a clinical
response). This effect of stimulation beyond asymptotic levels can alter
population to habituation in one or more control groups were included
subsequent behaviour (e.g., by delaying the onset of spontaneous recovery).
7. Within the same stimulus modality, the response decrement shows some stimulus in this review. The disorders that met this criterion were: Autism
specificity. To test for stimulus specificity/stimulus generalization, a second, Spectrum disorder, Fragile X syndrome, Schizophrenia, Parkinson’s
novel stimulus is presented and a comparison is made between the changes in the disease, Huntington’s disease, Attention Deficit Hyperactivity Disorder,
responses to the habituated stimulus and the novel stimulus. In many paradigms
Tourette’s syndrome, and Migraine. Despite the diverse etiology of
(e.g., developmental studies of language acquisition) this test has been
improperly termed a dishabituation test rather than a stimulus generalization
these disorders the degree of habituation alteration correlates with
test, its proper name. symptom severity in most of the disorders suggesting that under-
8. Presentation of a different stimulus results in an increase of the decremented standing the alterations in habituation might lead to new approaches to
response to the original stimulus. This phenomenon is termed “dishabituation.” It understanding, diagnosing, and treating these disorders. To our
is important to note that the proper test for dishabituation is an increase in
knowledge, the neuropsychiatric disorders reviewed here represent all
response to the original stimulus and not an increase in response to the
dishabituating stimulus (see point #7 above). Indeed, the dishabituating stimulus disorders for which there are five or more studies examining habitua-
by itself need not even trigger the response on its own. tion in human patient populations.
9. Upon repeated application of the dishabituating stimulus, the amount of
dishabituation produced decreases (“habituation of dishabituation”).
3. Study selection criteria
10. Some stimulus repetition protocols may result in properties of the response
decrement (e.g., more rapid rehabituation than baseline, smaller initial responses
than baseline, smaller mean responses than baseline, less frequent responses than This work heavily focuses on studies investigating non-associative
baseline) that last hours, days or weeks. This persistence of aspects of habituation learning alterations by comparing differences in response plasticity to
is termed long-term habituation. repeated stimulation in two or more groups. To delimit the scope this
review and provide a cohesive narrative, we excluded studies of habi-
tuation to drugs in addiction research. For disorders with pre-existing
different stimuli and training paradigms (Giles and Rankin, 2009;
reviews examining habituation alterations (e.g., ASD, Schizophrenia,
Rankin and Broster, 1992). Although studies using animal models have
Migraine), the reviews are briefly summarized and work published
revealed that both short- and long-term forms of habituation can be
since the most recent review are covered in detail. For disorders
observed (Castellucci et al., 1978), this review will focus on short-term
without a pre-existing review focused on alterations in habituation all
habituation reflecting the focus of the clinical literature to date. While
studies are reviewed.
short-term habituation develops within a single training session, long-
We have included only articles whose authors explicitly stated they
term habituation persists across training sessions and requires spaced
were investigating altered habituation in a neuropsychiatric disorder
training and protein synthesis for its production and maintenance
group compared to one or more control groups. However, it is im-
(Ramaswami, 2014; Rankin et al., 2009). Despite being the simplest
portant to note that any response change due to repeated non-asso-
form of learning there is very little known about the cellular mechan-
ciative stimulation is the sum of putatively independent underlying
isms of underlying habituation. Studies using Aplysia and rats show that
sensitization (incremental) and habituation (decremental) processes
short-term habituation can result from homosynaptic depression of
which are integrated to produce the final behavioural response (Groves
excitatory neurotransmission (Armitage and Siegelbaum, 1998;
and Thompson, 1970). Therefore, the observed changes in habituation
Castellucci et al., 1970; Castellucci and Kandel, 1974; Farel and
discussed here could in principle reflect changes in sensitization.
Thompson, 1976; Kupfermann et al., 1970; Weber et al., 2002) and
studies using Drosophila have shown that habituation can also manifest
4. Methods for studying habituation in humans
at the network-level by potentiation of inhibitory synapses (Das et al.,
2011; Glanzman, 2011).
The training paradigms and methods used to study habituation in
Consistent with the ubiquity, adaptive importance, and diversity of
humans are as diverse as the diseases and disorders they have been used
underlying mechanisms of habituation, habituation abnormalities have
to study. In order to facilitate accessibility to a broader scientific au-
been implicated in numerous etiologically diverse neuropsychiatric
dience we have provided a description of the common methods used to
disorders. The purpose of this review is to bring together accounts of
study habituation in adult humans: acoustic startle, event-related po-
habituation and neurological/neuropsychiatric disorders with the hope
tentials, electrodermal activity, and functional magnetic resonance
that this will lead to insights about both habituation, and the neu-
imaging (Table 2). The methods described in Table 2 are not ex-
ropsychiatric disorders in which habituation is altered. It is our hope
haustive, but rather represent the most common methods that re-
that this review will serve as a resource for both clinicians and basic
searchers build upon when designing more complex habituation

287
 T.A. McDiarmid et al.
Table 2
A brief description of common methods for the analysis of habituation in humans.

Common paradigm titles Brief description of method Commonly used eliciting stimuli Response metrics Detailed Studies using this
description of method to detect
method abnormal habituation

Startle reflex habituation or Intense stimuli are presented to induce a startle response: Usually brief intense auditory stimuli (loud Behavioural output (most commonly the Davis (1984), Koch Geyer and Braff
Acoustic Startle Reflex eye-lid closure (blink) and a contraction of facial, neck, tones presented through headphones). probability of blinking). Electromyographic (EMG) (1999) (1982), Braff et al.
(ASR) habituation and skeletal muscles. Habituation is observed as a Somatosensory and visual stimuli may also recording of the orbicularis oculi muscle (1992), Meincke et al.
decrease in startle response magnitude and/or probability be used to elicit a startle response. responsible for the blink reflex is common.a (2004)
with repeated stimulation. Recording ERPs (described above) following startle-
inducing stimuli is also common.
Event-related potential (ERP) Stimuli are presented to participants while event-related Simple discrete auditory, visual, and Voltage (i.e., microvolts) is measured from several Luck (2012) Coppola et al. (2013),
habituation or changes in voltage are measured from several electrodes somatosensory stimuli, as well as various different areas across the scalp (e.g., frontal, de Tommaso et al.
Cortical evoked potential placed across the scalp (i.e. Electroencephalography). nociceptive stimuli. Complex visual stimuli parietal, etc.). Various components of the ERP may (2014)
habituation Habituation is observed as a decrease in the latency or (e.g., checkerboard patterns) be isolated and analyzed individually. For example
amplitude of various components of the ERP wave with the negative deflection that occurs ∼100 ms after
repeated stimulation. the stimulus (N100) or the positive deflection that
occurs ∼300 ms after the stimulus (P300)b
Electrodermal activity (EDA) Stimuli (usually weak auditory tones) are presented to Simple discrete auditory, visual, Changes in skin conductance (i.e., micro Siemens) Dawson et al. Schoen et al. (2008)
habituation, participants in a standard laboratory or clinical setting. somatosensory stimuli, as well as various generated by eccrine sweat glands is measured (2007), Boucsein
288

Event-related skin Stimulus-evoked changes in skin conductance are nociceptive stimuli using two electrodes placed on the skin of the hands (2012)
conductance response measured. Habituation is observed as a decrease in the or fingers
(ER-SCR) habituation, or probability or magnitude of skin conductance response
Skin conductance with repeated stimulation.
orienting response
(SCOR) habituationc
Functional magnetic Stimuli are presented to participants inside the MRI Simple discrete auditory and visual stimuli BOLD contrast Breiter et al. Holt et al. (2005),
resonance imaging scanner via computer screens and speakers. Stimulus- (e.g., tones and shapes), complex visual (1996), Plichta Kleinhans et al. (2009)
(fMRI), Blood oxygen evoked BOLD contrast responses are recorded throughout stimuli (e.g., emotive faces) et al. (2014)
level stimulus repetitions. Habituation is observed as a decrease
dependent (BOLD) in evoked BOLD contrast with repeated stimulation
contrast habituation, or

Neuroscience and Biobehavioral Reviews 80 (2017) 286–305

Specific brain region
habituation (e.g.,
amygdala habituation)d

We have also provided references where a detailed description of the method can be found as well as examples from this review where the method has been used to detect abnormal habituation in the context of a disease or disorder.
a
The EMG blink response induced by weak stimuli that do not induce a startle response (e.g. supraorbital electrical stimulation) is also common (see Penders and Delwaide, 1971). The R2 component of the blink response EMG is most often
studied because it shows the greatest amount of habituation.
b
Magnetoencephalography (MEG) is often used to measure event related field (ERF) habituation in order to gain greater spatial resolution compared to EEG.
c
Galvanic Skin Response is an antiquated term referring to electrodermal activity, the term is no longer used for reasons discussed in Boucsein (2012).
d
Also referred to as fMRI adaptation, repetition suppression, and repetition attenuation.
T.A. McDiarmid et al.
paradigms.
5. Impaired habituation is an endophenotype of Autism Spectrum
Disorder
Autism Spectrum Disorder (ASD) is a heterogeneous neurodeve-
lopmental disorder characterized by fixated interests, inflexible rou-
tines, stereotyped behaviours, as well as difficulties with communica-
tion and social interactions. Despite the large phenotypic variation
present within the autism spectrum, improper processing of sensory
stimuli appears to be a shared phenomenon that has recently been
added to the list of diagnostic criteria (American Psychiatric
Association, 2013; Sinclair et al., 2017). Over 96% of individuals with
ASD report hypo- or hypersensitivity to stimuli across sensory mod-
alities (Crane et al., 2009; Leekam et al., 2007; Minshew et al., 2002;
Sinclair et al., 2017). Indeed, hypersensitivity to sensory stimuli is so
common in ASD it has inspired the influential “altered salience” and
“intense world” theories of ASD (Markram et al., 2007; Ramachandran
and Oberman, 2006). These and other “hyperarousal” or similar “de-
creased inhibition” theories suggest 1) children with ASD are more
easily aroused by sensory stimuli and/or 2) that they show reduced
habituation to repeated stimuli compared to other children
(Ramaswami, 2014; Rogers and Ozonoff, 2005). In support of these
theories, a variety of studies employing different stimulation paradigms
and modalities suggest that habituation deficits arise early in the de-
velopment of ASD and persist into adulthood.
Face-processing deficits are among the earliest reported social def-
icits in ASD. When repeatedly presented images of faces typically-de-
veloping children will habituate to the images by decreasing the
amount of time spent looking at each stimulus. Assessing the duration
of face-directed gaze, Webb et al. (2010) showed that 18–30 month-old
children with ASD, and their siblings, take longer to habituate to images
of faces than age-matched controls. These findings provide evidence for
decreased habituation at the earliest age that ASD can be reliably di-
agnosed, but deficits in habituation may be present even earlier in
development. An EEG study showed that 9-month-old infants at high
risk for ASD (i.e., possessing an older sibling diagnosed with ASD)
displayed decreased habituation of auditory evoked potentials when
compared to age matched low-risk controls (Guiraud et al., 2011).
Behavioural and electrophysiological studies of habituation in
adolescents and adults with ASD have provided less consistent results
due to increased heterogeneity of age in the patient population and the
diversity of stimulus presentation paradigms employed. In an attempt
to address this, an electrodermal study first separated adolescents with
ASD into high-arousal or low-arousal subgroups based on their resting
skin conductance before administering several blocks of stimuli across
all sensory modalities. This study revealed a trend where the high
arousal ASD subgroup showed reduced habituation while the low
arousal ASD subgroup displayed enhanced habituation, as compared to
controls (Schoen et al., 2008). Importantly, this study demonstrates the
large differences that can exist for individual habituation patterns
within the heterogeneous ASD group. Further investigation of habi-
tuation in ASD has come from recent studies primarily focused on
measures of sensorimotor gating (e.g., pre-pulse inhibition or P50
suppression). Many of these studies use an acoustic startle paradigm
where acoustic tones are delivered to participants through headphones
and the subsequent eye-blink response is recorded directly by ob-
servation or by electromyography (EMG). A range of results have been
obtained from subjecting ASD individuals to this procedure, including
reduced habituation (Perry et al., 2007), increased sensitization
(Madsen et al., 2014), as well as increased baseline response followed
by normal habituation (Kohl et al., 2014; Takahashi et al., 2016). It is
likely that the conflicting findings arise from a combination of the
heterogeneity of the patient populations and differences in stimulus
presentation paradigms used (Sinclair et al., 2017). Despite contra-
dictory findings, recent behavioural and electrophysiological studies
289
Neuroscience and Biobehavioral Reviews 80 (2017) 286–305
provide support for the notion that habituation deficits arise early in the
development of ASD and persist into adulthood.
The newest approach for investigating abnormal habituation in ASD
comes from a series of fMRI studies assessing the functional neural
correlates of face processing deficits. Hypotheses describing the neural
circuitry underlying abnormal face processing in ASD have centered on
hyperexcitability of the amygdala to social stimuli. However, studies
examining amygdala activity in response to social stimuli in ASD pa-
tients have found both increased activity (Dalton et al., 2005; Nacewicz
et al., 2006) and decreased activity (Ashwin et al., 2007; Critchley
et al., 2000). In a seminal paper, Kleinhans et al. (2009) hypothesized
that the amygdala response to social stimuli in ASD patients could be
best characterized not by simple over- or under-activation, but instead
by decreased neural habituation. In other words, while the amygdala
response to faces habituates in healthy controls (Fischer et al., 2003),
they expected this response to exhibit little plasticity in ASD in-
dividuals. To test this, Kleinhans et al. (2009) employed a paradigm
where adult ASD patients and controls were shown two sets of neutral
faces in two sets of fMRI scanning runs. In the first scanning run both
groups showed similar levels of amygdala activation while in the
second the authors observed significantly greater activation in the
amygdala of ASD patients. Importantly, the authors show that the
amygdala activation in the ASD group never exceeded the activation in
the control group. Instead, while amygdala activity in the control group
decreased with repeated stimulation, activity in the ASD group did not.
Intriguingly, post-hoc analysis demonstrated that the habituation im-
pairment correlated with the level of social dysfunction in the ASD
individuals (Kleinhans et al., 2009). This study illustrates a recurring
issue between brain activity measures (i.e. ERPs, BOLD, EMG) and
habituation. Many brain activity measures rely on averaging multiple
scans to get a detailed picture of activity in different brain areas.
However, processing the data this way lends itself to simple inter-
pretations of hyper- or hypo-activity and may mask underlying ab-
normalities in plasticity such as habituation.
This finding of reduced amygdala habituation to faces in ASD has
provoked several follow-up studies investigating the extent and nature
of this deficit. Swartz et al. (2013) found deficits in amygdala habi-
tuation in youth with ASD using shorter presentation times as well as a
correlation between reduced habituation and social dysfunction. Fur-
ther, Swartz et al. (2013) found that decreased amygdala habituation in
the ASD group correlated with decreased activation in the ventromedial
Prefrontal Cortex (vmPFC) compared to controls, suggesting a possible
role for reduced vmPFC activity in the habituation deficits observed.
Indeed, the vmPFC has been implicated in top-down inhibition of the
amygdala during habituation (Hare et al., 2008). Another study from
the same group investigated the relationship between face habituation
in ASD patients and serotonin transporter genotype (Wiggins et al.,
2014). They found that individuals with ASD and low-expressing ser-
otonin transporter genotypes displayed greater deficits in amygdala
habituation to sad faces than ASD individuals with high-expressing
serotonin transporter genotypes. While these findings offer some me-
chanistic insight into the cause of decreased habituation in ASD, they
are more broadly impactful as they illustrate that the endophenotype of
habituation deficits in ASD may be more amenable to genetic analysis
than the heterogeneous ASD diagnosis itself. Green et al. (2015) also
showed decreased amygdala habituation in ASD patients that coincided
with decreased functional connectivity between the vmPFC and the
amygdala. Intriguingly, the severity of decreased habituation correlated
with increased sensory overresponsivity (Green et al., 2015). Finally, in
a recent study Kleinhans et al. (2016) replicated their initial finding of
reduced amygdala habituation in response to emotional faces and
showed that this deficit was specific to face processing as ASD in-
dividuals showed normal habituation to images of houses.
It is interesting to note that recent studies strongly support the no-
tion of decreased habituation in ASD, while older reports produced
conflicting results (Rogers and Ozonoff, 2005). One possibility is that
T.A. McDiarmid et al.
the diagnostic criteria for ASD have shifted the phenotypes of the pa-
tient population. Indeed, sensory overresponsivity has only recently
been added to the DSM-V criteria for ASD (American Psychiatric
Association, 2013; Lai et al., 2013). Since patients with ASD do not all
necessarily display decreased habituation, further analysis into the
cause of individual differences for this deficit is needed. Habituation
measurements could become an additional tool of differential diag-
nostics for subtypes within the ASD group. Given the evidence for de-
creased habituation as a tractable endophenotype of this disorder
(Guiraud et al., 2011; Webb et al., 2010; Wiggins et al., 2014) further
molecular and systems level examinations into how this simple form of
learning and sensory filtering is disrupted in ASD are warranted.
In summary, habituation impairments have been observed in ASD
throughout development and in adulthood. Several recent fMRI studies
have demonstrated impaired amygdala habituation to emotive faces in
ASD and made positive correlations between with habituation impair-
ment and social dysfunction. This is intriguing as it suggests that the
habituation impairment is not limited to simple stimuli (e.g., auditory
tones) but extends to complex social stimuli (i.e., faces) and may have
social repercussions. Further, these studies have begun to elucidate the
neural circuit and genetic abnormalities that lead to impaired amygdala
habituation in ASD. Given the prevalence of drugs used to treat certain
aspects of ASD (e.g., antipsychotics used to treat irritability), it will be
interesting to see if these drugs also affect habituation.
6. Habituation deficits in Fragile X Syndrome
Fragile X syndrome (FXS) is the most common monogenic cause of
intellectual disability (Hagerman et al., 2009; O’Donnell and Warren,
2002; Sinclair et al., 2017). FXS is caused by expansion and hy-
permethylation of CGC repeats in the promoter region of the Fragile X
mental retardation 1 (FMR1) gene which results in reduced or abolished
FMRP expression. Decreased FMR1 expression has been shown to alter
protein synthesis dependent synaptic plasticity and dendritic spine
growth, processes critical to early neurodevelopment (Greenough et al.,
2001; Irwin et al., 2001).
FXS is also the leading monogenic cause of Autism Spectrum
Disorder (ASD) with approximately 15–33% of individuals with FXS
meeting the diagnostic criteria for ASD and 5% of ASD cases being
attributed to FXS (Bailey et al., 1998; Cohen et al., 2005). Additionally,
individuals with FXS alone (i.e., not comorbid with ASD) often show
characteristics reminiscent of ASD, including deficits in social beha-
viour, delays in language development, sensory over-responsivity, and
decreased habituation (Barnes et al., 2009; Berry-Kravis et al., 2007;
Hagerman et al., 1986, 1991; Roberts et al., 2007; Rotschafer and
Razak, 2014).
In a preliminary study, the electrodermal responses to repeatedly
presented olfactory, auditory, visual, tactile, and vestibular stimuli
were compared between individuals with FXS and normal controls.
Consistent with the habituation phenotype of ASD, individuals with FXS
displayed both enhanced electrodermal responses at baseline and de-
creased habituation compared to controls. Intriguingly, this habituation
phenotype was observed across stimulus modalities and was shown to
correlate with the level of FMRP expression (Miller et al., 1999).
Studies using electroencephalogram recordings (EEG) have also
found reduced habituation in FXS. Castrén et al. (2003) reported in-
creased magnitude and decreased habituation of N100 event-related
potentials in response to trains of auditory tones in individuals with
FXS. This finding was subsequently supported by three additional EEG
studies that also found reduced N100 habituation in response to re-
peatedly presented auditory tones (Ethridge et al., 2016; Schneider
et al., 2013; Van der Molen et al., 2012). Reduced N1 habituation was
also associated with parent reports of heightened sensory sensitivities
and social communication deficits (Ethridge et al., 2016). The present
findings should be interpreted cautiously, however, as other groups
have failed to dishabituate N100 response decrements (Barry et al.,
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Neuroscience and Biobehavioral Reviews 80 (2017) 286–305
1992). Interestingly, treatment with the broad spectrum antibiotic
minocycline has recently been shown to increase global functioning,
improve performance on tests of anxiety and mood-related behaviours,
as well as ameliorate EEG-recorded sensory abnormalities and reduced
habituation in individuals with FXS (Leigh et al., 2013; Schneider et al.,
2013). Using a mouse model of FXS, Bilousova et al. (2009) demon-
strated that minocycline promotes dendritic spine maturation and im-
proves behavioural deficits by inhibiting the enzyme MMP-9 (matrix
metalloproteinase 9). This has led to the suggestion that a similar me-
chanism may underlie the clinical improvements that occur following
minocycline treatment of FXS (Schneider et al., 2013). Indeed, a recent
study reported that FMR1 knock-out mice displayed decreased auditory
N1 habituation that was rescued by additional knock-out of MMP9
(Lovelace et al., 2016).
Another FXS deficit that has been studied in the context of habi-
tuation is the propensity to avoid eye contact (Cohen et al., 1989;
Farzin et al., 2009). A recent study by Bruno et al. (2014) compared
individuals with FXS to individuals with idiopathic developmental
delay, intellectual disability, or learning disability but no known ge-
netic or neurological disorder, on an fMRI habituation task. Participants
were repeatedly presented 4 different neutral faces in two orientations
such that half of the images were looking at the participant while the
other half were looking away. In individuals with FXS the BOLD re-
sponse in the cingulate gyrus, fusiform gyrus, and frontal cortex ex-
hibited significantly reduced habituation (and significant sensitization)
to all faces as compared to controls. So, despite the observation that
individuals with FXS avoid eye contact, they showed reduced habi-
tuation to faces regardless of whether the images are looking at the
participant or not (Bruno et al., 2014). It is also interesting to note that,
similar to Miller et al. (1999), Bruno et al. also found a correlation
between increased FMRP expression and decreased habituation.
Taken together, studies of habituation and FXS point to habituation
deficits that are present across sensory modalities, and like individuals
with ASD, occur along with basic sensory abnormalities as well as more
complex deficits in social processing of face stimuli. To date, there have
been no studies assessing habituation abnormalities throughout devel-
opment in FXS. Recent studies have shown that minocycline treatment
induced marked improvements in symptom severity that correlate with
improved habituation in individuals with FXS. These studies are pro-
mising as they suggest the neurodevelopmental abnormalities that re-
sult in reduced plasticity in FXS are reversible with an acute pharma-
cological intervention. Moving forward, it will be interesting to
determine whether other monogenic disorders associated with altered
neurodevelopment and autistic symptoms (e.g. Rett syndrome, Cowden
syndrome, etc.) display impaired habituation as well.
7. Habituation deficits in Schizophrenia
Impaired attention and information processing are among the core
cognitive deficits of schizophrenia. Indeed, a reduced ability to filter
out irrelevant stimuli has been implicated in schizophrenia for over a
century (Bleuler, 1950) and remains a prominent research interest
today. Much of the modern interest in this field has been fueled by the
influential clinical reports of McGhie and Chapman (1961), who pro-
posed that people must be able to filter out information in order to
maintain “perceptual constancy” in a world of otherwise chaotic
overstimulation (Geyer and Braff, 1987). They further suggested that
impaired inhibitory processing in schizophrenia leads to “sensory
overload” and subsequent “cognitive fragmentation.” Research into the
cause of impaired inhibitory processing in schizophrenia has focused on
cataloguing and understanding impairments in two related yet distinct
phenomena: sensorimotor gating and habituation. Sensorimotor gating
is the ability of a neural system to selectively filter intero- and ex-
teroceptive stimuli that drive a motor reflex. It is often operationally
defined as pre-pulse inhibition (PPI), i.e., the ability of a weak pre-
stimulus (pre-pulse) to transiently inhibit the response to a closely
T.A. McDiarmid et al.
following strong stimulus (test pulse) (Braff et al., 1992). Habituation,
in contrast, is a decrement in response following repeated presentations
of the same stimulus. While sensorimotor gating and habituation are
both forms of inhibition, the former is often considered to be pre-at-
tentive and un-learned whereas the latter is an established form of
learning with specific behavioural characteristics (Braff et al., 2001,
1992; Swerdlow et al., 2008; although see Quednow et al., 2006a who
suggest that PPI may be subject to learning; Rankin et al., 2009 and
Table 1).
Since the pioneering work of Geyer and Braff (1982), most studies of
habituation and schizophrenia have used the acoustic startle response
as a paradigm to understand habituation. Using this paradigm, Geyer
and Braff (1982) demonstrated that schizophrenic patients habituate
more slowly to acoustic startle as compared to normal controls. This
study represents an unfortunately rare example of the use of con-
sistently spaced identical stimuli to directly compare habituation be-
tween patients, patient controls, and healthy controls without any in-
tervening irregular stimuli or changes in stimulus intensity.
Despite the clarity of this initial finding, results of subsequent stu-
dies have been inconsistent. Several groups replicated Geyer and Braff’s
original finding of significant habituation deficits in schizophrenia pa-
tients (Akdag et al., 2003; Bolino et al., 1994, 1992; Greenwood et al.,
2011; Hokyo et al., 2010; Ludewig et al., 2003; Moriwaki et al., 2009;
Parwani et al., 2000; Takahashi et al., 2008); Several more found a non-
significant trend towards decreased habituation (Braff et al., 1992;
Ludewig et al., 2002a, 2002b; Perry et al., 2002, 2001), while others
did not detect habituation deficits in schizophrenia (Braff et al., 1999;
Cadenhead et al., 2000; Csomor et al., 2009; Hasenkamp et al., 2011;
Kumari et al., 2002, 2000; Quednow et al., 2008, 2006b; Wang et al.,
2013; Xue et al., 2012).
Two key factors have been suggested to account for this discrepancy
(Meincke et al., 2004). First, the majority of these studies were opti-
mized to assess PPI rather than habituation. In the most common design
the average response to a block of identical pulses at the beginning of
the experiment is compared to that elicited by a second block of pulses
at the end of the experiment in order to assess habituation (Fig. 1). In
between these two habituation blocks, PPI is assessed by delivering
weak pre-pulses followed by test pulses that are identical to the pulses
delivered in the habituation blocks. During this phase the interstimulus
interval is varied and test pulses can occur with or without pre-pulses,
and the intensity of prepulse can vary. In this protocol habituation is
usually assessed by comparing the average response in Block 1 (Base-
line Response) with the average response in Block 3 (Habituated Re-
sponse). While this protocol has become standard practice for assessing
habituation it is problematic because altering the interstimulus interval
and stimulus intensity within the same period (as in the middle pre-
pulse block) are known to affect habituation (e.g., see Broster and
Rankin, 1994; Meincke et al., 2004; Rankin et al., 2009). A further
concern is that condensing habituation trials into blocks fails to take
into account any potential initial sensitization to the startle-eliciting
stimuli. The possibility of an initial period of sensitization prior to ha-
bituation is well-documented (Groves and Thompson, 1970; Rankin
et al., 2009). Indeed, Meincke et al. (2004) found habituation deficits in
schizophrenic patients but only when the effects of sensitization were
removed from analysis. Therefore, intermixed pre-pulse and habitua-
tion stimuli, masking due to sensitization, and bias due to focus on PPI
are issues that may underlie the inconsistencies in the literature. Fi-
nally, using blocks of responses to assess habituation can mask a dif-
ference if habituation is very rapid (often the biggest response decre-
ment is over the first 2–3 responses) and if the early responses are
averaged with decremented responses the actual decrement is mini-
mized or lost (i.e., Fig. 1, Block 1).
Unfortunately, the majority of studies of habituation phenomena in
schizophrenia over the last decade have been carried out without re-
gard for these issues in their experimental design. There have been
more than 30 studies focused on PPI of the acoustic startle reflex in
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Neuroscience and Biobehavioral Reviews 80 (2017) 286–305
schizophrenia published in the last ten years that continue to use pulse-
alone trials mixed with pre-pulse trials to assess habituation. It is per-
haps not surprising then that the results of these studies remain in-
consistent, with several finding impaired habituation, and others failing
to find significant differences between patients and controls. To prop-
erly assess habituation it is important to design studies in a way that
optimizes the proper assessment of habituation. One potential altera-
tion to the standard paradigm would be to increase the number of
pulse-alone stimuli delivered within the first block and assess response
plasticity within that block before pre-pulse pairings are delivered
(Lane et al., 2013). This would allow for a more direct analysis of short-
term habituation and mitigate the confounding effects of pre-pulse
stimuli.
Despite these issues, some of the recent PPI-intermixed startle ha-
bituation studies have found deficits in habituation and have made
intriguing correlations between habituation abnormalities and a variety
of genetic variants implicated in schizophrenia. Of note, a relatively
large study (81 schizophrenic patients and 71 controls) investigated the
relationship between decreased habituation and seven “top-ranked”
gene variants implicated in the etiology of schizophrenia (Hokyo et al.,
2010; Allen et al., 2008). There was a significant interaction, with pa-
tients homozygous for the schizophrenia-associated rs1019385 (T200G)
variant in the GRIN2B gene showing significantly decreased habituation
compared to controls. There were no interactions between the other
schizophrenia-associated gene variants and habituation (Hokyo et al.,
2010). Another large study by Greenwood et al. (2011) assessed 94
candidate genes associated with schizophrenia and evaluated whether
each gene associated with both the qualitative diagnosis of schizo-
phrenia as well as impaired habituation. Using a sample of 203 patients
with schizophrenia and 119 controls, impaired habituation was found
to be associated with mutations in the genes GRIN2B, NRG1, HTR2A,
COMT, NOS1AP, SLC6A1, GRID2, GRM2, and NEUROG1. Intriguingly,
many of the genes analyzed in this study have been shown to interact at
the molecular level and several displayed pleiotropy, with several single
gene mutations showing associations for multiple schizophrenia phe-
notypes (Greenwood et al., 2011). Overall, these studies support the
large body of research implicating dopaminergic and glutamatergic
signaling abnormalities in the cognitive deficits of schizophrenia as well
as a role for these neurotransmitter systems in impaired habituation in
schizophrenia.
Although the acoustic startle paradigm has been the most commonly
used paradigm to study habituation phenomena in schizophrenia, sev-
eral groups have also investigated habituation using other behavioural
and physiological responses. Perry et al. (2009) documented decreased
habituation of locomotor activity in an open-field paradigm using an
automated human behavioural pattern monitor. An early series of stu-
dies examined differences in the electrodermal skin conductance or-
ienting response between schizophrenic patients and controls. The most
reliable finding from these studies is that a large portion of schizo-
phrenic patients do not respond to the series of repeatedly presented
stimuli during a habituation task (Bernstein et al., 1982; Dawson et al.,
2007). More central to this review is the relatively understudied finding
that the schizophrenic patients who did respond to the repeated tones
displayed abnormal skin conductance habituation (Dawson et al., 2007;
Gruzelier and Venables, 1972; Schiffer et al., 1996). However, some
electrodermal studies found reduced rates of habituation while others
found more rapid rates of habituation. This discrepancy may have been
caused by a lack of controlling for differences in baseline responsive-
ness and differences in scoring methods between groups (Bernstein
et al., 1982; Dawson et al., 2007; Depue and Fowles, 1973; Spohn and
Patterson, 1979). Still, it is worth noting that the degree to which ha-
bituation was reduced in these patients was correlated with poor per-
formance on several neuropsychological tests, including the Wisconsin
Card Sorting Task and Trail Making tests (Bartfai et al., 1987; Schiffer
et al., 1996).
Holt et al. (2005) were the first to use fMRI to examine whether the
T.A. McDiarmid et al. Neuroscience and Biobehavioral Reviews 80 (2017) 286–305

Fig. 1. Typical protocol for assessing habituation and sensorimotor gating within the same time period. The mean eye-blink response intensity to a block of identical test pulses (usually
auditory) at the beginning of the experiment is compared to that elicited by a final block of identical test pulses at the end of the experiment in order to assess habituation. In between
these blocks are the prepulse inhibition trials containing test pulses at various interstimulus intervals, some preceded by weaker pre-pulses, some not. Additionally, some protocols also
vary the intensity of pre-pulses (not shown in figure). This design is problematic given that it a) may mask potential sensitization that occurs initially (see response to block 1) and b)
incorporates a pre-pulse inhibition block which means that both the interstimulus interval and stimulus intensity are changed throughout the experiment. Such changes in the manner of
stimulus presentation are known to significantly affect habituation profiles (Meincke et al., 2004; Rankin et al., 2009). Of note, both the interstimulus interval and stimulus intensity may
vary drastically from study to study. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

decreased habituation found in schizophrenia would also manifest at
the level of activity in specific brain regions. In particular, they ex-
amined the hemodynamic response of the medial temporal lobe − in-
cluding the amygdala, hippocampus, and parahippocampal gyrus to
repeated presentations of fearful faces in male schizophrenic patients
and controls. As hypothesized, patients with schizophrenia failed to
display temporal lobe habituation in any area, in response to fearful
faces whereas control subjects displayed neural habituation in the
anterior right hippocampus (Holt et al., 2005). Based on the large body
of research in schizophrenia demonstrating sensorimotor gating deficits
(Braff et al., 1992; Light and Braff, 2005) and the evidence for per-
turbed processing of faces (Javitt, 2009), Williams et al. (2013) hy-
pothesized that neural habituation in response to neutral faces may also
be reduced in the primary visual cortex and the fusiform face area
(FFA). Interestingly, patients with schizophrenia displayed reduced
habituation of both the hippocampus and primary visual cortex but not
the FFA. These habituation deficits were specific to faces, as they were
not observed when participants viewed objects (Williams et al., 2013).
In a direct follow-up study by the same group, Blackford et al. (2015)
showed that the same sample of schizophrenic patients also displayed
selectively impaired habituation to opposite-gender faces in the
amygdala, visual cortex, and hippocampus, providing evidence for
abnormal processing of more complex social information such as
gender-based out-group bias. Importantly, all of these studies correlated
decreased neural habituation with diminished performance on beha-
vioural tests of either visual memory, verbal memory, or social im-
pairments (Blackford et al., 2015; Holt et al., 2005; Williams et al.,
2013). Taken together, these findings suggest that habituation in dif-
ferent brain areas may be mediated by different mechanisms, some but
not all of which are disrupted in schizophrenia. It is also interesting to
note that, similar to ASD, the most consistent recent evidence for de-
creased habituation in schizophrenia comes from fMRI studies
examining the functional neural correlates of face processing. Indeed,
abnormal neural habituation to social stimuli may represent a trans-
diagnostic biomarker for social impairment (Blackford et al., 2015).
In summary, there have been more studies focused on habituation
abnormalities in schizophrenia than in any other neurological disease.
Despite this extensive research program, the acoustic startle habitua-
tion studies that constitute the majority of the work in this field remain
inconsistent. The current standard of assessing acoustic startle habi-
tuation with intermixed pre-pulse stimuli has confounding variables
that precludes unambiguous interpretation of the results. More studies
focused directly on habituation to repeated stimuli are needed. Further,
comparing habituation responses across other sensory modalities will
allow for a more holistic picture of how this elementary form of
learning is disrupted in schizophrenia. Recent fMRI studies measuring
neural habituation to complex face stimuli provide more evidence for
decreased habituation in schizophrenia. A more complete depiction of
how habituation is disrupted in schizophrenia will greatly facilitate the
utility of this learning deficit as a phenotype for basic research into the
underlying cause of the disorder.
8. Enhanced habituation may underlie perturbed attention in
Attention Deficit Hyperactivity Disorder
Attention-deficit hyperactivity disorder (ADHD) is characterized by
deficits in executive function not limited to attention, memory, and
response inhibition. Few ADHD studies exist which are optimally de-
signed to assess habituation phenomena. Of the studies which do report
habituation phenomena in ADHD, several find enhanced habituation
(Iaboni et al., 1997; Shibagaki et al., 1993; Zahn and Kruesi, 1993)
others deficient habituation (Jansiewicz et al., 2004; Massa and
O’Desky, 2012), whereas several other studies report no habituation
abnormalities (Conzelmann et al., 2010; Feifel et al., 2009; Holstein

292
T.A. McDiarmid et al.
et al., 2013; Ornitz et al., 1999, 1997, 1992).
Reports of enhanced habituation come from experimental para-
digms which appear to involve more active decisions by participants
and which include participants with comorbid diagnoses [i.e., conduct
disorder (CD) and oppositional defiant disorder (ODD)]. Using a re-
petitive motor task in which participants were rewarded each time they
inactivated a constantly moving target, Iaboni et al. (1997) demon-
strated that the heart rate of ADHD children habituated more quickly to
rewards than controls. In this same paradigm, removing rewards ap-
peared to dishabituate the heart rate of ADHD children to levels similar
to controls. It is worth noting that infant cognition studies also use heart
rate to measure visual attention albeit with a different paradigm
(Colombo et al., 2010).
Using an acoustic reaction-time task, Zahn and Kruesi (1993) de-
monstrated that, compared to controls, children with disruptive beha-
viour disorder showed accelerated habituation of skin conductance
responses to signal stimuli but not to passive stimuli. Analysis of di-
agnostic subgroups (i.e., ADHD, ODD, CD) further showed that en-
hanced habituation manifested equally across the disruptive behaviour
spectrum. It is curious that in both of these studies, enhanced habi-
tuation was selectively observed in tasks that demanded sustained at-
tention. This is consistent with reports that attention deficits in ADHD
are primarily attributed to impaired early top-down processes as op-
posed to late top-down or bottom-up processes (Conzelmann et al.,
2010; Hawk et al., 2003). To complicate this picture, however, Herpertz
et al. (2003, 2001) found that children with CD and children comorbid
with both CD and ADHD exhibited reduced basal skin conductance
responses and enhanced habituation to passive acoustic stimuli (both
orienting and startling) compared to children with ADHD alone or to
normal controls. While heart rate and eyeblink response were also
measured, the authors did not assess these metrics for habituation,
making it difficult to compare these results to Iaboni et al. (1997).
Moreover, Shibagaki et al. (1993) found that ADHD children showed
reduced basal skin conductance responses and more rapid habituation
to passive but not to active acoustic stimuli. However, this study did not
report whether ADHD children were comorbid with other conditions.
A number of other studies suggest that novelty and task qualities
such as colour are quicker to lose their stimulating effects in ADHD
individuals (reviewed in Douglas, 1999; although see Tegelbeckers
et al., 2015). While it is tempting to interpret these results as examples
of enhanced habituation, it is important to note that these studies are
not systematically designed to measure a graded, stimulus-driven re-
sponse decrement within a particular behaviour which is a criterion of
habituation. Rather, these studies coarsely compare motor activity or
task performance across two experimental conditions (e.g., reading
performance with high- vs. low-stimulation or coloured vs. non-co-
loured stimuli). Taking these results with caution, Lloyd et al. (2014)
have suggested that rapid habituation to reinforcers may account for
the performance deficits ADHD individuals display in tasks requiring
sustained attention and associative memory. According to this theory,
excessively rapid habituation diminishes the efficacy of reinforcers and,
thereby, interferes with the acquisition of reward contingencies leading
to overall task impairment. Curiously, this implies that the difficulties
in higher forms of learning normally associated with ADHD may in fact
be explained by enhancements in lower forms of learning. Lloyd et al.
(2014) provide evidence that stimulant medication slows habituation to
reinforcers and suggests this may account for their frequent use in
treating ADHD. The suggestion that habituation may modulate instru-
mental learning is in line with its presumed role in attention and further
stresses the importance of habituation to normal cognitive function. At
present, more direct studies examining the rate of habituation to re-
peatedly presented reinforcers are needed to support this view.
In contrast to findings of enhanced habituation, Jansiewicz et al.
(2004) and Massa and O’Desky (2012) reported reduced visual habi-
tuation in children and adults with ADHD as indexed by a Troxler task.
In this task, individuals are instructed to focus on a central fixation
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point while a competing dot lies in the peripheral field of view. In-
dividuals are asked to report when the peripheral dot disappears (as is
expected). In comparison to age-matched controls, Jansiewicz et al.
(2004) and Massa and O’Desky (2012) found that children and adults
with ADHD took longer to report fading of the peripheral stimulus. The
authors hypothesize that decreased habituation to peripheral stimuli
may account for the common difficulty ADHD individuals have with
focusing on task-relevant stimuli. While it is tempting to describe these
results within a habituation framework, the design of the Troxler
paradigm precludes the observation of a graded decrement in response
to successive stimulus presentations that is the cornerstone of habi-
tuation phenomena.
In sum, reduced, intact, and enhanced habituation has been re-
ported in ADHD. These assessments of learning phenotype derive al-
most exclusively from studies using skin conductance response and
heart rate measures and, as such, would greatly benefit if additional
measures were used (e.g., fMRI). Both reduced and enhanced habitua-
tion have been suggested to contribute to the impairments in attention
and associative learning observed in ADHD. There are, however, several
issues with the method used to assess habituation in ADHD that make
interpretation of the learning phenotype difficult. These include inter-
mittent assessment of PPI, group-specific differences in response base-
line, and block-based analysis which confounds sensitization effects
(although see Herpertz et al., 2003). Importantly and revealingly, all of
the studies that reported no habituation phenotype measured habitua-
tion of the electromyographical eyeblink response in tandem with PPI.
Future studies which address these issues are required to clarify the link
between enhanced habituation and deficits in attention and instru-
mental learning in ADHD.
9. Tourette’s Syndrome − habituation as therapy?
Tourette’s Syndrome (TS) is a heritable neuropsychiatric disorder
diagnosed in childhood and characterized by motor and vocal tics.
While its biological basis remains elusive, dysfunction of cortico-striato-
pallido-thalamic pathways are thought to be involved (Felling and
Singer, 2011). The majority of people with TS report that their tics are
often preceded by aversive physical sensations. Described by patients as
an itch, pressure, tension, or ache (Reese et al., 2014), these sensations
are known in the research community as premonitory urges; their in-
tensity has been shown to increase during bouts of tics after which, they
decrease (Brandt et al., 2016). Of note, many TS patients report that tic
execution provides relief from these urges. Since tics can be voluntarily
suppressed, it has been suggested that habituation to premonitory urges
may provide a means to treat and reduce tic behaviour. On this basis,
two behavioural therapies − habit reversal therapy and exposure with
response prevention therapy − have been employed with remarkable
levels of success to reduce the severity of tic behaviour (Hwang et al.,
2012). Both of these treatments encourage the patient to refrain from
ticking in response to the premonitory urge. However, while exposure
with response prevention therapy more directly promotes habituation
to premonitory urges by encouraging patients to expose themselves to
premonitory urges, habit reversal therapy is designed to replace the tic
with another behaviour that competes with or delays the tic.
In support of the urge habituation hypothesis, a series of studies
have found that exposure with response prevention therapy and habit
reversal therapy reduced the intensity of premonitory urges within
and/or across treatment sessions (Capriotti et al., 2014; Hoogduin et al.,
1997; Verdellen et al., 2008). However, another study reported rela-
tively stable urge intensity levels across treatment sessions in spite of
the fact that tic behaviour was still significantly diminished (Specht
et al., 2013). Of note, these studies used different self-report meth-
odologies to measure premonitory urges including the Premonitory
Urge for Tics Scale (Capriotti et al., 2014), Subjective Units of Distress
Scale (Verdellen et al., 2008), Visual Analogue Scale (Hoogduin et al.,
1997) and the Urge Thermometer (Specht et al., 2013). If urge intensity
T.A. McDiarmid et al.
remains unaltered after treatment (Specht et al., 2013), a more complex
mechanism than habituation may underlie the efficacy of habit reversal
therapy and exposure with response prevention therapy. Indeed, while
habituation to premonitory urges may contribute to exposure with re-
sponse prevention therapy and habit reversal therapy, another possi-
bility is that the contingency between the tic behaviour (i.e., the con-
ditioned response) and cessation of premonitory urges (i.e., the
conditioned stimulus) is disrupted (Capriotti et al., 2014; Specht et al.,
2013). Given the heterogeneity of TS and the fact that a spectrum of
learning strategies exists across individuals within operant conditioning
paradigms (Morrison et al., 2015), it is possible that both non-asso-
ciative and associative learning processes contribute to treatment out-
come either within one individual or in a manner that segregates across
patients.
Using a simulated premonitory urge model involving air puffs de-
livered to the eye, Beetsma et al. (2013) demonstrated that having
participants tick (deliberately blink) following an urge (operationalized
as air puffs on the eye) reduced the subjective annoyance of the urge,
while simultaneously extending the duration of the R2 EMG component
(of the eye muscles) and blocking its habituation. Although this study
used healthy participants, the extended duration and impaired habi-
tuation of R2 EMG component matched that of another electro-
physiological study using TS patients (Smith and Lees, 1989). In this
study, paired electrical stimulation of the supraorbital nerve produced
an R2 EMG response which was more resistant to habituation in TS
patients than controls. Reduced habituation was also found in another
study which used a reaction time (i.e., go/no) paradigm in which
acoustic startle stimuli were presented at the same time and un-
expectedly with signal stimuli (Gironell et al., 2000). Although TS pa-
tients exhibited a greater EMG response, a greater degree of spread with
respect to responsive muscles, and reduced habituation compared to
controls, it is important to note that variable interstimulus intervals
were used in this study, a feature known to affect the rate of habituation
(Rankin and Broster, 1992).
Pharmacological studies have also advanced our understanding of
the relationship between premonitory urges and behavioural tics.
Injection of botulinum toxin has been shown to diminish both tic be-
haviour and premonitory urges (Kwak et al., 2000; Marras et al., 2001).
While these observations can be explained as pharmacological facil-
itation of habituation and/or extinction, the selective efficacy of eco-
pipam (a dopamine antagonist) to reduce tics but not urges presents a
challenge to the urge habituation hypothesis (Gilbert et al., 2014).
Together, these suggest that multiple processes may exist for treating tic
behaviour some of which are independent of premonitory urges
(Houghton et al., 2014).
Another series of studies investigated more directly whether there is
abnormal habituation behaviour in TS patients using startle response
paradigms. Using a light and sound stimulation paradigm, Bock and
Goldberger (1985) found that the tonic but not phasic skin conductance
response of TS patients habituated more slowly than controls: i.e., both
the initial response level and habituation rate was smaller than in
controls. Analyzing four single-case studies of TS patients, Turpin and
Powell (1984) found intact habituation of the skin conductance re-
sponse to auditory stimulation both between and across sessions. Fi-
nally, a series of acoustic startle studies assessing EMG habituation of
the eye and other muscles found no differences between TS patients and
controls (Castellanos et al., 1996; Sachdev et al., 1997; Swerdlow et al.,
2001) although see Stell et al. (1995) who reported no acoustic startle
habituation in 2 out of 8 TS patients but normal habituation in all
controls. However, it is important to note that by virtue of their pro-
tocol design or focus on PPI, these latter studies did not maintain a
consistent stimulation regime either in terms of stimulus strength or
interval.
In sum, reduced and intact habituation phenotypes have been re-
ported in TS populations, using skin conductance and electro-
myographical response measures. Habituation mechanisms have also
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Neuroscience and Biobehavioral Reviews 80 (2017) 286–305
been proposed to underlie the efficacy of certain behavioural therapies
used to treat urge-tic behaviour in TS although this notion has been
challenged by recent pharmacological and behavioral-therapy studies.
Various theories have been proposed to account for reduced habitua-
tion in TS, including increased excitability of brainstem interneurons
(Smith and Lees, 1989), increased dopaminergic tone (Gironell et al.,
2000), and interference of habituation by negative reinforcement of tics
(Beetsma et al., 2013). In addition, there is some evidence that tics may
reflect exaggerated startle reflexes which are evoked by inappropriate
stimuli (Turpin, 1983). As such, reduced habituation may reflect, in
part, generalization of anxiolytic or aversive stimuli. However, there
are a number of aspects of tic behaviour that cannot be easily explained
by a simple habituation model, including the obvious fact that tics may
be voluntarily suppressed [for review of tics as exaggerated startle, see
Turpin (1983)]. To further complicate this picture, Smith and Lees
(1989) found reduced habituation in approximately half of TS patients
with no clinical differences distinguishing them from patients ex-
hibiting normal habituation. Future studies will have to take into ac-
count individual differences when assessing the contribution of learning
processes to TS phenotypes.
10. Habituation deficits in Parkinson’s Disease − a diagnostic tool
Parkinson’s disease (PD) is the most common neurodegenerative
movement disorder and is characterized by resting tremor, bradyki-
nesia, rigidity, and postural instability. The disease also presents with
non-motor symptoms, including psychiatric (e.g., apathy, depression),
sensory, and sleep disturbances, as well as cognitive impairments.
These non-motor symptoms often precede the movement impairments
by several years and may develop progressively. Diagnosis of PD can
only be confirmed post mortem by the observation of dopaminergic cell
loss and Lewy body pathology in the substantia nigra pars compacta
(Stern et al., 2012; Volta et al., 2015; Weintraub et al., 2008).
The study of habituation in PD is unique because decreased habi-
tuation has been used as a diagnostic tool for several decades. The
glabellar tap sign is a clinical test where a patient is repeatedly tapped
on the forehead to elicit a blink response. Normally, the blink reflex will
habituate after a few stimulus repetitions, but in PD there is virtually no
response decrement to repeated glabellar taps (Garland, 1952; Pearce
et al., 1968; Rao et al., 2003; Rushworth, 1962). Habituation deficits in
PD have also been shown to manifest in the eye-blink response to re-
peated supraorbital electrical stimulation. In particular, the late R2
EMG component of the blink reflex does not habituate as readily in PD
as it does in controls (Penders and Delwaide, 1971; Rushworth, 1962).
Importantly, the R2 component can still habituate in PD patients, but
patients must be stimulated at a much higher frequency (i.e. shorter
interstimulus interval) than controls (Esteban and Giménez-Roldán,
1975; Ferguson et al., 1978; Messina et al., 1972; Penders and
Delwaide, 1971; Rushworth, 1962; Sanna and Messina, 1967). The
degree to which R2 habituation is altered in PD has also been positively
correlated with the severity of motor symptoms and this has provided
the basis for its use as a diagnostic tool (Matsumoto et al., 1992;
Messina et al., 1972; Penders and Delwaide, 1971). Interestingly,
treatment with amantadine and L-DOPA, but not anticholinergic drugs,
has been shown to normalize habituation in PD patients (Klawans and
Goodwin, 1969; Messina et al., 1972; Penders and Delwaide, 1971; Rey
et al., 1996). These medications, indeed, may explain the failure of
more recent studies to identify acoustic startle eye-blink habituation
deficits in PD patients since neither the type nor dose of medications
used was controlled (Kofler et al., 2001; Putzki et al., 2008; Zoetmulder
et al., 2014). These findings have led to the notion that reduced blink
reflex habituation in PD stems from degeneration of dopaminergic
neurons in the substantia nigra. This hypothesis has received support
from animal studies demonstrating that 6-hydroxydopamine lesion of
dopaminergic cells in the substantia nigra leads to an increase in in-
hibitory substantia nigra output to the superior colliculus. Increased
T.A. McDiarmid et al.
inhibition of the superior colliculus results in decreased excitation of
tonically active nucleus raphe magnus neurons which, in turn, de-
creases tonic inhibition of trigeminal neuronal responsiveness, which
leads to blink reflex hyperexcitability and reduced habituation (Basso
et al., 1996, 1993; Basso and Evinger, 1996).
Habituation of various components of event-related potentials
evoked by auditory stimuli have also been studied in PD. Teo et al.
(1997) found decreased habituation of the P1 component of the audi-
tory evoked potential in PD patients. Moreover, post-hoc analysis re-
vealed the degree of decreased habituation to be correlated with the
severity of symptoms. It should be noted, however, that decreased ha-
bituation was again found only at shorter interstimulus intervals but
not longer intervals and that averaged blocks of only two stimuli were
used to measure habituation (Teo et al., 1997). In a follow-up study,
Teo et al. (1998) investigated whether decreased auditory P1 habitua-
tion would be altered by bilateral pallidotomy, an antiquated treatment
for dyskinesia in advanced PD. Pallidotomy involves ablating a portion
of the globus pallidus by means of a surgically implanted electrical
probe (Ghika et al., 1999; Merello et al., 2001). In line with their pre-
vious study, Teo et al. (1998) found a pre-operative deficit in P1 ha-
bituation that correlated with symptom severity. Following bilateral
pallidotomy, patients showed a significant improvement in both habi-
tuation and symptom severity. However, these results are contentious
considering bilateral pallidotomy has subsequently been shown to in-
duce severe apathy and depression along with slurred, unintelligible
speech, drooling, and pseudobulbar palsy (Ghika et al., 1999; Merello
et al., 2001). Indeed, the treatment efficacy of bilateral pallidotomy is
so low and the side effects are so severe that it is rarely performed
today, with deep brain stimulation being the surgical treatment of
choice (Ghika et al., 1999; Hickey and Stacy, 2016; Merello et al.,
2001). Still, the findings of Teo et al. (1998) are intriguing as they re-
present an extremely rare opportunity to examine the effects of a
controlled neural lesion on habituation in humans.
Combining auditory stimulation with electroencephalography,
Jiang et al. (2000) found that PD patients exhibited increased latency of
N100 and P300 potentials, reduced P300 amplitude, and no response
decrement of N100 latency. A similar study published the same year
also found reduced amplitude and increased latency of P300 potentials
in PD and further found that P300 amplitude did not habituate in PD
patients (Tsuchiya et al., 2000). Further analysis revealed P300 ab-
normalities to be correlated with decreased performance on the Wis-
consin Card Sorting Task, a common test of executive functions. A third
independent study published in the same year also reported reduced
P300 habituation and impaired performance on the Wisconsin Card
Sorting Task (Hozumi et al., 2000). However, in contrast to the two
studies discussed previously, Hozumi et al. (2000) reported reduced
P300 latency in PD patients. The consistent observation of P300 ab-
normalities in PD − be they latency or readiness to habituation − has
prompted the suggestion that P300 waveform may provide a clinically
useful marker for frontal lobe dysfunction in this neuropsychiatric po-
pulation (Tsuchiya et al., 2000).
Abnormal habituation in PD may also contribute to primary central
pain (i.e., pain with no identified cause) found in some PD patients.
Using nociceptive laser “pinprick” stimuli, Schestatsky et al. (2007)
demonstrated that PD patients with primary central pain have lower
laser pinprick thresholds, higher laser-evoked potential (LEP) ampli-
tudes, and reduced habituation of laser-induced skin conductance re-
sponses. Interestingly, L-DOPA normalized LEP amplitudes which are
recorded centrally, but did not normalize the reduced habituation of
laser-induced skin conductance responses, which are recorded periph-
erally. Taken together, these findings suggest that PD patients with
primary central pain suffer an abnormal modulation of afferent pain
inputs to autonomic centers (Schestatsky et al., 2007).
Late-stage PD patients also often have trouble maintaining balance,
making injurious falls more common. One way to measure a patient’s
ability to balance is to use dynamic posturography in which a platform
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causes the toes to be stretched upwards. In this procedure, the center of
mass (COM) is measured to indicate shifts in posture and ability to
regain balance. Using this paradigm, Nanhoe-Mahabier et al. (2012)
noted that acutely unmedicated PD patients had a larger COM dis-
placement in response to the first unexpected balance perturbation and
a slower rate of habituation to repeated balance perturbations than
controls. Importantly, two earlier studies by the same group did not find
balance perturbation habituation abnormalities in PD, likely because
they tested patients on medication and used blocked averages to mea-
sure habituation (Bloem et al., 1998; Nanhoe-Mahabier et al., 2012;
Visser et al., 2010). The first trial reaction and slowed rate of habi-
tuation assessed using standardized dynamic posturography may offer a
more reliable diagnostic tool for impaired balance than the commonly
employed retropulsion test (Nanhoe-Mahabier et al., 2012).
Overall, the literature on PD points to multimodal habituation
deficits that manifest in a variety of physiological responses. Unlike
other disorders, interest into habituation abnormalities in PD has ori-
ginated in a clinical context for diagnostic purposes. Pharmacological
studies in patients and animal models suggest reduced blink reflex
habituation in PD stems from degeneration of dopaminergic neurons in
the substantia nigra that leads to subsequent reduced tonic inhibition of
the trigeminal nerve. It is interesting to note that all blink reflex studies
only found habituation deficits when PD patients were not taking L-
DOPA, whereas all auditory potential studies found habituation deficits
in patients taking L-DOPA, without testing when patients were off of
medication. This suggests that distinct mechanisms may underlie ha-
bituation deficits in the eye-blink reflex and the auditory-evoked elec-
troencephalographic response in PD patients.
11. Habituation deficits in Huntington’s Disease
Huntington’s Disease (HD) is a neurodegenerative disorder char-
acterized by impairments in motor coordination and cognition. In
particular, muscle chorea often manifests in the extremities and gra-
dually progresses to all muscles. Expansion of CAG triplet repeats in the
Huntingtin gene is thought to underlie this phenotype by contributing
to the progressive degeneration of medium spiny neurons within the
striatum (Lemiere et al., 2004; Ross and Tabrizi, 2011).
Electromyographical (EMG) studies suggest that the gross psycho-
motor abnormalities associated with HD may also manifest as ab-
normalities in the habituation of reflex responses. All studies assessing
the eye-blink response evoked by repeated supraorbital electrical sti-
mulation have found significantly enhanced habituation of the late
component (R2) in patients as compared to controls (Agostino et al.,
1988; Caraceni et al., 1976; Esteban and Giménez-Roldán, 1975, 1981;
Ferguson et al., 1978). In contrast, no significant abnormalities have
been shown in the rate at which the early component (R1) habituates.
This selectivity may simply reflect a more robust circuitry for the R1
component given that it does not readily succumb to habituation or
fatigue in healthy individuals (Lindquist and Brown, 2004). Of note, the
R1 component of the blink reflex occurs ipsilaterally through an oli-
gosynaptic pathway in the pons whereas the R2 component occurs bi-
laterally through polysynaptic connections.
In contrast with the foregoing studies which looked at the eye-blink
response, Abbruzzese et al. (1990) investigated the reflex response of
wrist muscles stimulated by repeated pneumatic motor torque. In ad-
dition to a delayed onset and reduced size, the late component (M2) of
the stretch reflex was found to be impaired in extent of habituation.
However, the authors note that a baseline confound may account for
this finding, given that the size of the M2 component was significantly
reduced in HD patients. One additional study assessing habituation of
electrodermal response of fingers to acoustic stimuli found no sig-
nificant difference between HD and normal controls (Iacono et al.,
1987). It is important to note that the modality of stimulation in these
last two studies (i.e., acoustic or tactile) was different than the pre-
ceding studies of the eyeblink reflex (i.e., electrical). Taken together,
T.A. McDiarmid et al.
these studies suggest that the impact of HD on habituation is selective
not only with respect to reflex type (i.e., wrist or eye-blink) but to
waveform component (i.e., short- or long-latency). The connection
between reflex habituation abnormalities and clinical state in HD re-
mains controversial. Esteban and Giménez-Roldán (1975) found no
association between degree clinical state and the R2 response whereas
Agostino et al. (1988) and Ferguson et al. (1978) report a positive
correlation between R2 habituation and chorea severity and duration
respectively.
In sum, in the relatively scant literature exploring habituation in HD
the majority of studies point towards an enhanced habituation pheno-
type. This observation of enhanced habituation is intriguing since re-
duced habituation is the most common habituation phenotype reported
across neuropsychiatric disorders. A more definitive assessment of this
learning phenotype will be provided when habituation is assessed using
paradigms other than electrodermal and electromyographical response
to acoustic/electrical stimuli. Enhanced habituation of the eye-blink
response in HD has been interpreted to reflect over-inhibition of do-
paminergic receptors in the striatum (Caraceni et al., 1976; Esteban and
Giménez-Roldán, 1975). In support of this theory, both apomorphine (a
dopamine receptor agonist) and nicotine (a dopamine stimulant) reduce
the amplitude of the eyeblink reflex and increase the latency of the R2
component in controls (Evinger et al., 1993).
12. Cyclic habituation abnormalities in episodic migraine
Migraine is a primary headache disorder characterized by recurrent
headache attacks accompanied by a hypersensitivity to visual, auditory,
and somatic stimuli. Most people afflicted experience episodic migraine
− a recurring cycle of sequential prodromal symptoms that start sev-
eral hours before the headache attack. Some people, however, develop
chronic migraine (i.e., ≥15 days of headache per month with at least
8 days of typical migraine headache) (de Tommaso et al., 2014). In at
least 20% of migraine patients headache attacks are preceded by
transient neurological symptoms called auras (Pietrobon and Striessnig,
2003). Auras are often visual disturbances but may also involve other
senses or disturb language (Pietrobon and Striessnig, 2003). Since there
are no obvious neuroanatomical abnormalities in those with the dis-
order, migraine is considered a functional brain disorder. Most theories
suggest migraines result from increased activation of the main pain
signaling system in the brain, the trigeminal vascular system (de
Tommaso et al., 2014; Pietrobon and Striessnig, 2003).
There is a large body of literature investigating habituation ab-
normalities in migraine that has been reviewed extensively (Coppola
et al., 2013, 2009; de Tommaso et al., 2014). As such, findings will be
discussed only briefly here.
The majority of studies have demonstrated that migraine patients
show no response decrement to repeated stimuli when tested during the
period between headache attacks (i.e., the interictal phase of episodic
migraine). More specifically, migraine patients typically display a
normal to low response to initial stimuli, followed by stable response
amplitude (i.e., no response decrement) or a slight response increase
(i.e., sensitization) after repeated stimulation. This abnormality is ob-
served in a large number of evoked potential studies that use visual,
somatosensory, and auditory stimulation paradigms and various re-
sponse metrics (Coppola et al., 2013, 2009; de Tommaso et al., 2014).
Habituation of evoked potentials induced by noxious stimuli, including
laser, thermal, and electrical stimulation of Aδ and C fibre nociceptors
has also been shown to be substantially reduced in migraine (de
Tommaso et al., 2014, 2005; Di Clemente et al., n.d.; Ferraro et al.,
2012; Katsarava et al., 2003). Further, reduced habituation of reflexive
behaviours (e.g. the blink reflex) in response to innocuous and noci-
ceptive stimuli has also been observed in migraine (Coppola et al.,
2013, 2009; de Tommaso et al., 2014). It should be noted however, that
numerous studies have failed to replicate the visual evoked potential
habituation deficit in migraine (Oelkers et al., 1999; Omland et al.,
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Neuroscience and Biobehavioral Reviews 80 (2017) 286–305
2016; Sand et al., 2009). The most frequently argued reason for this
inconsistency is lack of blinding to diagnosis, although this explanation
remains an area of debate (Brighina et al., 2016; de Tommaso et al.,
2014; Omland et al., 2016).
Interestingly, it appears that habituation abnormalities in migraine
patients vary with the cycle of their symptoms − namely, deficits are
associated with lapses in acute symptoms both in episodic and chronic
migraine patients. In episodic migraine, habituation of evoked poten-
tials is absent during the interictal phase. However, in the 12–24 h
preceding and during a migraine attack, evoked potential habituation
normalizes (Coppola et al., 2013, 2009; de Tommaso et al., 2014). In
line with these observations, chronic migraine patients who frequently
experience attacks display normal evoked field habituation, in a
manner reminiscent of episodic migraine patients during an attack
(Chen et al., 2011). Moreover, when these attacks become less frequent
chronic migraine patients begin to display a cyclic interictal evoked
field habituation deficit characteristic of episodic migraine (Chen et al.,
2012).
Although the neural basis of habituation abnormalities in migraine
remains largely unknown, a prevailing theory implicates thalamocor-
tical dysrhythmia (Coppola et al., 2007; de Tommaso et al., 2014).
Thalamocortical dysrhythmia refers to alterations in the frequency of
synchronous oscillatory firing between thalamic and cortical cells such
that they display putatively pathogenic low-frequency oscillations
(Llinás et al., 1999; Llinás and Steriade, 2006). Coppola et al. (2007)
has proposed that decreased serotonin input from the brainstem to the
thalamus and cortex causes thalamocortical dysrhythmia and subse-
quently decreased habituation in migraine. In support of this theory,
early high-frequency oscillations of somatosensory evoked potentials,
which are thought to reflect the firing of cholinergic thalamocortical
afferents, have decreased frequency between attacks (when habituation
is decreased) and normalize during attacks (when habituation is
normal) in migraine patients (Coppola et al., 2005; Sakuma et al.,
2004). Further, excitatory stimulation of the cortex using 10 Hz rTMS
normalized high-frequency oscillations and the interictal evoked po-
tential habituation deficit in migraine patients (Bohotin et al., 2002;
Coppola et al., 2012; Fumal et al., 2006). An fMRI study also demon-
strated that migraine patients had reduced habituation of BOLD con-
trast in response to trigeminal-nociceptive stimulation but normal ha-
bituation in response to olfactory stimulation, a discrepancy that the
authors attributed to the fact that olfactory pathways bypass the tha-
lamus (Stankewitz et al., 2013).
Overall, the cyclic polymodal habituation deficit observed in mi-
graine patients is intriguing. It would be interesting to see if habituation
observed in other disorders follow a similar cyclic correlation with
symptoms − i.e., if habituation impairments for a particular individual
get worse as their symptoms become more severe and vice-versa.
Further, the use of rTMS stimulation to test hypotheses about neural
circuit malfunction underlying impaired habituation is a further
strength of the Migraine literature that researchers of other neu-
ropsychiatric disorders might find useful. While the data supporting the
presence of thalamocortical dysrhythmia and subsequent habituation
disruption in migraine are compelling, it remains unclear how dys-
rhythmia would lead to activation of the trigeminovascular system and
induce a migraine attack. The cellular and molecular abnormalities that
may cause thalamocortical dysrhythmia also remain largely unknown.
Further independent replication of results, as well as additional neu-
roimaging and genetic studies will more clearly elucidate the nature
and implications of habituation deficits in the etiology of migraine.
13. Discussion
Abnormal habituation has been repeatedly observed in Autism
Spectrum Disorder, Fragile X syndrome, Schizophrenia, Parkinson’s
disease, Huntington’s disease, Attention Deficit Hyperactivity Disorder,
Tourette’s syndrome, and in Migraine. Depending on the disorder and
T.A. McDiarmid et al.
paradigm, habituation has been implicated as a cause, symptom, or
therapy. Abnormal habituation is predictive of symptom severity across
diverse neuropsychiatric disorders. Reduced habituation is the most
commonly reported phenotype across paradigms and disorders, al-
though enhanced habituation has also been observed. The exact cause
of altered habituation in any of the disorders is unknown, and remains
an area of extensive research. Remarkably, there are instances where
treatments have been found to normalize the habituation deficit present
in the disorder and several of its associated symptoms.
In addition to the disorders covered in this review there are reports
of decreased habituation in Epilepsy (Brazzo et al., 2011; Rogozea et al.,
1992), Down syndrome (Hepper and Shahidullah, 1992; Schafer and
Peeke, 1982), Panic disorder (Ludewig et al., 2005; Ludewig et al.,
2002a, 2002b; Roth et al., 1990) and Post-Traumatic Stress Disorder
(Gillette et al., 1997; Rothbaum et al., 2001). However, given the
limited number of studies, further research is needed for these disorders
in order to support these findings. Similar to Tourette’s Syndrome,
habituation has also been used as a treatment for Post Traumatic Stress
Disorder (Vaughan et al., 1994; Vaughan and Tarrier, 1992) and other
neuropsychiatric disorders. Although extinction rather than habituation
is more commonly thought to underlie exposure therapy, the two
learning processes share many fundamental characteristics and both are
likely to contribute to the attenuation of conditioned responses (for
review, see McSweeney and Swindell, 2002). Finally, it is interesting to
note that, in contrast to the disorders described in this review, habi-
tuation and attention appear to be spared in Alzheimer’s disease while
associative learning and memory are severely and progressively im-
paired (Hejl et al., 2004; Langley et al., 1998).
13.1. Considerations for the design and interpretation of habituation
experiments
It is important to point out that although many of the studies cov-
ered here report altered habituation, with the exception of acoustic
startle, very few demonstrate that the response decrement being studied
fits the criteria of habituation as outlined by Thompson and Spencer
(1966) and Rankin et al. (2009). A dishabituation test is the simplest
and most definitive way to determine if the response decrement being
measured is the result of habituation (i.e., learning) and not sensory
adaptation or motor fatigue. A second way to distinguish habituation
from sensory adaptation or motor fatigue is to assess spontaneous re-
covery from habituation which is faster following training at fast in-
terstimulus intervals and slower following training at slow inter-
stimulus intervals − this is the opposite of what would be expected if
the response decrement were due to fatigue or sensory adaptation
(Rankin et al., 2009). Finally, response specificity of the decrement can
be used to rule out sensory adaptation or motor fatigue (Rankin et al.,
2009). To be definitively called habituation the response decrement
being measured must pass one of these tests.
Across disorders, and in schizophrenia in particular, there has been
extensive focus on habituation of the acoustic startle response. Further
studies assessing habituation across sensory modalities are necessary in
order to assess to what extent habituation impairment is a global or
local phenomenon. Indeed, there are examples where one type of ha-
bituation is altered in a disease but not another (e.g., in Parkinson’s
disease eye-blink habituation is altered but not acoustic startle habi-
tuation).
Taking all of these points into consideration the ideal way to com-
pare habituation between a patient and control group is to: 1)
Administer repeated identical stimuli at a regular interstimulus interval
and measure the response of each participant to each stimulus; 2)
Calculate the group mean response to each stimulus; 3) Test different
interstimulus intervals in different experimental sessions in order to
determine if habituation is altered across interstimulus intervals or only
at certain interstimulus intervals (as is the case in Parkinson’s disease);
4) Test different stimulus modalities at different times (e.g. auditory,
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Neuroscience and Biobehavioral Reviews 80 (2017) 286–305
visual, somatosensory, etc.). 5) Perform a dishabituation test, an in-
terstimulus interval dependent spontaneous recovery test or a stimulus
generalization test to confirm that the response decrement is indeed
habituation. Although this would be ideal, we recognize that in studies
with clinical populations these types of parametric studies are not al-
ways possible and some response measures do not lend themselves to
this type of analysis. The challenge then becomes to optimize the design
for the response and population being studied. For example, in imaging
studies where individual responses are highly variable, it is important
to average together as few responses as possible in order to fully ob-
serve the course and range of response plasticity (i.e., learning) pro-
duced by stimulus repetition (Kleinhans et al., 2009). When there are
differences in initial sensitization between groups (as in some Schizo-
phrenia acoustic startle paradigms) comparing the final response to the
first trial, instead of comparing final responses to the first block will be
more accurate (see Meincke et al., 2004). It is hoped that when re-
searchers consider the behavioural characteristics of habituation they
will design experiments and analyze data in ways that take these
characteristics into account.
In addition to experimental design and analysis considerations, we
have suggested guidelines for the classification of altered habituation
phenotypes (Fig. 2). We have drawn idealized lines that represent
prototypic habituation curves for hypothetical data, and illustrate the
most common ways that normal habituation can be altered. All of the
different phenotypes provided in Fig. 2 are important distinctions, and
offer a systematic nomenclature to classify the ways that habituation
can be altered in a disease (beyond the label of “altered” or “ab-
normal”). Use of this classification system will allow for more targeted
replication experiments using both clinical populations and animal
models in order to understand what disease-relevant cellular and mo-
lecular changes result in a particular habituation phenotype. Fig. 2A
presents a typical habituation curve depicting a decrease in behavioural
response to repeated stimulation. While most habituation curves follow
a negative exponential decrement as displayed here, linear habituation
curves have also been observed. In addition, a period of sensitization to
the first few stimuli before habituation begins has also been observed
(Groves and Thompson, 1970). The vertical red line in Fig. 2A re-
presents the administration of a dishabituating stimulus (usually a
novel or noxious stimulus) to demonstrate that the observed response
decrement is due to habituation and not sensory adaption or motor
fatigue. The response increase following the dishabituating stimulus
can be partial, full, or greater than the baseline initial response (Rankin
et al., 2009). Fig. 2B illustrates curves that have the same initial re-
sponse magnitude and that show increased and decreased habituation
phenotypes. In the decreased habituation group, the ability to decrease
the magnitude and/or probability of responding to repeated stimulation
is significantly reduced. The opposite is true for the increased habi-
tuation example. In these phenotypes the change in response magnitude
from initial to final is lower in the decreased habituation group and
higher in the increased habituation group when compared to control.
Fig. 2C shows curves that have the same initial response magnitude and
the same final level of habituation, however they have different rates of
decrement and thus have increased and decreased rate of habituation
phenotypes. In the increased habituation rate example, the total
amount of habituation (or change in response from initial to final) is the
same as control but the rate of decrement or slope is higher/faster than
control. The opposite is true for the decreased habituation rate ex-
ample. Fig. 2D illustrates hyper- & hypo-responsive phenotypes. These
curves show different initial response levels, and different final re-
sponse levels, but the same rate of decrement and total amount of de-
crement. This is not considered a habituation deficit per se, but as a
change in sensitivity to the stimulus such that the organism is hyper- or
hypo-responsive without any change in the plasticity of the response.
Sometimes responses do not decrement and Fig. 2E illustrates no re-
sponse decrement phenotypes and floor effects. In the no response de-
crement example, there is no significant decrement in response in the
T.A. McDiarmid et al. Neuroscience and Biobehavioral Reviews 80 (2017) 286–305

A Prototypic Habituation Curve B Increased & Decreased

15 Habituation Phenotypes
Control/normal 15
Control/normal
Response Parameter

Response Parameter
Decreased habituation
10 10 Increased habituation

5 5

0 0
0 5 10 15 0 2 4 6 8 10
Stimulus # Stimulus #
Increased & Decreased
C Habituation Rate Phenotypes D Hyper- & Hyporesponsive
15 15
Phenotypes
Control/normal Control/normal
Response Parameter

Response Parameter
Decreased Hyperresponsive
10 habtuation 10 Hyporresponsive
rate
Increased
5 habituation 5
rate

0 0
0 2 4 6 8 10 0 2 4 6 8 10
Stimulus # Stimulus #

No Response Decrement
E Phenotypes & Floor Effect
F Disrupted Habituation
15 15
Control/normal Control/normal
Response Parameter

Response Parameter

No response decrement Disrupted habituation

10 No response decrement & 10 with normal initial
hyperesponsive response
Disrupted habituation
No response decrement & with abnormal initital
5 hyporesponsive 5
response
Floor effect
0 0
0 2 4 6 8 10 0 2 4 6 8 10
Simulus # Stimulus #

Fig. 2. Guidelines for interpreting habituation curves. A) An idealized prototypic habituation curve depicting a decrease in behavioural response to repeated stimulation. Note: The
dishabituation portion of the curve has been excluded from the remaining figure panels for clarity. B) Increased and decreased habituation phenotypes. In the decreased habituation
example (red), the ability of the experimental group to habituate, or decrease the magnitude and/or probability of responding to repeated stimulation is significantly reduced. The
opposite is true for the increased habituation example (blue). C) Increased and decreased rate of habituation phenotypes. In the increased habituation rate example, the total amount of
habituation (or change in response from initial to final) is the same as control but the rate of decrement is higher/faster than control (blue). The opposite is true for the decreased
habituation rate example (red). D) Hyper- & hyporesponsive phenotypes. E) No response decrement phenotypes and floor effects. In the no response decrement example, there is no
significant decrement in response in the experimental group throughout the training session. This may occur along with a hyper- or hyporesponsive phenotype. In the case of a floor effect,
the experimental group does not respond to the same stimulation as the control group. F) Disrupted Habituation. In this case the experimental group shows no predictable pattern of
response to repeated stimulation.

experimental curve throughout the training session. This may occur
along with a hyper- or hyporesponsive phenotype. In the case of a floor
effect, the experimental group does not respond to the stimulation.
Floor effects make it impossible to determine whether there is a habi-
tuation abnormality in the experimental group without further study
(i.e., finding a stimulus that both the control and experimental group
respond to). Finally, some responses do not change systematically over
the course of repeated stimulation; thus, Fig. 2F illustrates what we are
calling disrupted habituation. In this case the experimental curve shows
no predictable pattern in response to repeated stimulation. This may be
due to increased variability in the experimental group, suggesting the
possibility that an increased number of participants would allow for
detection of the true habituation phenotype. However, it is also possible
that the experimental group displays a replicable disrupted habituation
phenotype. If this is the case the results should be reported as “dis-
rupted” habituation and not “decreased habituation” or “no response
decrement”. Of course, combinations of two or more of these pheno-
types are possible. For example, if the experimental group has a sig-
nificantly larger initial response than control followed by a significantly
increased rate of habituation compared to control then it should be
reported as such.
Having a systematic nomenclature to describe habituation curves is
the first step to more systematically categorizing habituation deficits in
neuropsychiatric disorders. The second critical factor is determining the
best way to display and analyze the data: in particular, whether to
present raw or normalized data. Indeed, in many of the studies on ha-
bituation raw data are not presented, instead they are normalized
across groups (i.e. presented as a percentage or proportion decrement
relative to the initial score). This may be done because initial response
levels are different between groups, or because of high levels of
variability between subjects. It is important to recognize that normal-
izing may influence the conclusions drawn from the data. In Fig. 3 we
present both raw and normalized data and demonstrate the ways that
normalizing can alter the interpretation of the data. Although normal-
izing the initial response across groups is common, it masks any dif-
ferences in initial response between the experimental and control
group. In the context of disease it is important to determine if the pa-
tient group is more or less sensitive to stimuli than controls. Fig. 3A
shows hypothetical habituation curves of raw data for a control group
displaying a prototypic habituation curve, an experimental group

298
T.A. McDiarmid et al. Neuroscience and Biobehavioral Reviews 80 (2017) 286–305

Normalized to Initial Response

A Raw Data B (Proportion of Initial Response)

Proportion of Initial Response

15 1.5
Control/normal Control/normal
Response Parameter

Hyperresponsive Hyperresponsive/
10 Hyporesponsive 1.0 decreased habituation
Hyporesponsive/
Floor effect
increased habituation
5 0.5 Floor effect/
no response decrement

0 0.0
0 2 4 6 8 10 0 2 4 6 8 10
Stimulus # Stimulus #

Raw Data Habituation Percent Change Habituation

C D [(Initial - Final) / Initial] x 100
(Initial - Final Response)
15 100
Control/normal Control/normal

Response Parameter
Response Parameter
Absolute Change in

Hyperresponsive 80 Hyperresponsive/

% Change in
10
decreased habituation
Hyporesponsive 60 Hyporesponsive/
Floor effect increased habituation
40
5 Floor effect
20

0 0
Group Group
Initial Response Before
E Standardizing
15
Control/normal
Response Parameter

Hyperresponsive
10 Hyporesponsive
Floor effect

0
Group

Fig. 3. Considerations for the assessment of habituation using normalized initial responses vs. raw data. A) Hypothetical ‘raw data’ habituation curves for a control group displaying a
prototypic habituation curve, an experimental group displaying a hyperresponsive phenotype (red), an experimental group displaying a hyporesponsive phenotype (blue), and an
experimental group displaying a floor effect (green). B) The same “raw” data from panel A) normalized to the initial response of each group. C) Habituation phenotypes when habituation
is assessed as the absolute change in response from initial to final response. D) Habituation phenotypes when habituation is assessed as the percent change in response from initial to final.
E) Raw Data for initial responses.

displaying a hyperresponsive phenotype, an experimental group dis-
playing a hyporesponsive phenotype, and an experimental group dis-
playing a floor effect. Fig. 3B shows the same data normalized to the
initial response of each group by setting each group’s initial response
1.0 and subsequent responses are plotted as a proportion of the group’s
initial response. Note the changes in the slopes or rate of decrement of
the hyper- and hypo-responsive groups. In the raw data they appear to
show the same rates of response decrement whereas in the normalized
data they appear to show significantly different rates of decrement; in
addition, note the large change in the floor effect group. One way to
assess habituation is to calculate the change in response magnitude
from the initial response to the final response: Fig. 3 shows this cal-
culation using raw data (3C) or normalized data (3D). From Fig. 3C the
conclusion would be that there is no difference in habituation across the
groups; however, normalizing the same data would yield significant
differences in habituation across all of the groups. Thus, normalizing
alters the interpretation of the data. Note that we have discussed tests
that compare initial to final levels of response to assess habituation
because they are by far the most commonly used. Alternative methods
to assess habituation, including repeated measures analysis of variance,
group regression, and individual regression and their relative strengths
and weaknesses are discussed at length in Petrinovich and Widaman
(1984).
While it may be necessary to normalize data in order to mean-
ingfully compare groups, this treatment of data removes any
information about differences in initial response. As such, we suggest
that it is important to always include raw initial response data as shown
in Fig. 3E if normalizing is performed. Having knowledge about the raw
initial response allows for a more complete interpretation of the nor-
malized data. Ideally, all raw data would also be presented (For ex-
ample see Davis and File, 1984; Typlt et al., 2013). Awareness of these
alternative interpretations of habituation may allow for more consistent
observations across studies and may reconcile apparent discrepancies in
the literature.
13.2. Future directions
Given that multiple mechanisms underlie short-term habituation at
different interstimulus intervals, future studies should test at multiple
interstimulus intervals to give a better picture of how habituation is
disrupted in each disorder. Similarly, fMRI studies of habituation could
expand their analysis beyond their a priori determined regions of in-
terest (Lombardo et al., 2009). The possibility remains that if whole
brain analysis were conducted, other areas would show habituation
deficits as well. Another way in which future studies could strengthen
our understanding of how habituation is altered in disease is to provide
further analysis of individual differences of people who display ab-
normal habituation versus those who do not (Sinclair et al., 2017).
There are correlations between symptom severity and the degree of
decreased habituation in many disorders − but the correlations are not

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perfect. Further analysis of people with severe symptoms but normal
habituation and vice versa may shed light on the cause of decreased
habituation and its role in the disorder. In addition, correlating specific
types of habituation deficit (i.e., final habituated level vs. habituation
rate) with other characteristics of a disorder may identify specific ha-
bituation phenotypes for diagnostic use in a clinical setting. With the
constantly decreasing cost of genome sequencing it will soon be feasible
to conduct genome sequencing and link different mutations in a patient
population (or individual in the case of rare variants) to decreased
habituation.
13.3. The significance of altered habituation in neuropsychiatric disorders
This review should make it clear that there is not a single central
core mechanism of habituation that mediates response plasticity to all
types of stimuli in all situations. It is far more likely that habituation to
stimuli in different sensory modalities is mediated by different circuits
and/or mechanisms. In light of this, it is not surprising that the results
of studies claiming “impaired habituation in disorder x” are incon-
sistent. Limiting interpretations to the paradigm studied will un-
doubtedly yield more replicable results. For example, the title “im-
paired short-term acoustic startle habituation but intact short-term
mechanosensory habituation is disorder x” is more descriptive and
immediately provides testable hypotheses. It is our hope, that by
bringing together all disorders where habituation is studied we can
influence the largest audience to promote a more systematic and precise
description of how habituation is altered in a disorder. Acknowledging
this diversity of habituation mechanisms and providing more precise
descriptions not only helps to reconcile the apparent inconsistencies in
the field but will also guide research that 1) produces reliable diag-
nostic markers and 2) elucidates the neurobiology underlying habi-
tuation in both intact and disease-compromised nervous systems.
There are hundreds of papers documenting decreased habituation
across several neurological diseases, so what does reduced habituation
tell you about the disorder? Generally, reduced habituation suggests the
hypothesis that one or more sets of synapses in a neural circuit gov-
erning the behaviour is/are less plastic in response to repeated stimu-
lation. This could be due to altered neuronal development (i.e., the
circuit is not built the same way) or it could be due to disease specific
changes in synaptic gene expression or even degeneration of the neu-
rons comprising the circuit. Decreased short-term habituation could
suggest either an impaired ability to decrease excitatory neuro-
transmitter release, or a deficit in the ability to increase the firing of
inhibitory neurons onto the circuit governing the behaviour. Reduced
habituation on its own tells you little about the underlying pathology of
the disorder. However, when integrated with other knowledge about
the disorder of interest (e.g., loss of dopaminergic cells in the substantia
nigra in Parkinson’s disease, or mutations in the FMR1 gene leading to a
neurodevelopmental increase in synapse number) it is possible to gen-
erate specific hypotheses about the cause of altered habituation in a
particular disorder. For example, a loss of dopaminergic cells in the
substantia nigra induces a cascade of changes resulting in a decrease in
tonic inhibition of trigeminal neurons and thus decreased short-term
eye-blink habituation (Basso et al., 1996, 1993; Basso and Evinger,
1996). Further cellular and circuit level explanations of how habitua-
tion is decreased in a disorder will allow for targeted treatments to
normalize habituation and potentially more complex forms of learning
and memory.
Given that habituation is a ubiquitous and behaviourally conserved
learning process involved in filtering out irrelevant stimuli it is almost
certainly important for normal cognitive function. The most common
argument for the clinical significance of reduced habituation is that,
because it allows an organism to focus on important stimuli, habitua-
tion is a requisite for more complex forms of learning and memory.
Indeed, habituation has been implicated in a variety of associative
learning phenomena not limited to classical conditioning, operant
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Neuroscience and Biobehavioral Reviews 80 (2017) 286–305
conditioning, and extinction (Cevik, 2014; Lloyd et al., 2014;
McSweeney and Swindell, 2002). Therefore, habituation is predicted to
have broad and diverse clinical implications when disrupted. If the
relationships between habituation and other forms of learning are ex-
perimentally supported, we would expect that ameliorating habituation
impairments should lead to functional improvements in other tests of
learning and memory in neuropsychiatric populations. In line with this
notion, decreased habituation often correlates with symptom severity
across neuropsychiatric disorders, including deficits in more complex
forms of learning and memory (e.g., the Wisconsin Card Sorting Task).
Moreover, treatments that improve short-term habituation also improve
other symptoms and cognitive deficits observed in neuropsychiatric
disorders. Further, several studies suggest that infants with decreased
habituation have greater instances of central nervous system dysfunc-
tion and lower adult IQ scores as adults.
14. Concluding remarks
Abnormal habituation has been repeatedly observed in numerous
etiologically diverse neuropsychiatric disorders. Across several dis-
orders, abnormal habituation is predictive of symptom severity. Yet, for
most disorders remarkably little is known about what causes the ha-
bituation deficit and even less is known about the mechanisms under-
lying the relationship between habituation alterations and neu-
ropsychiatric symptoms. Conclusions about the role of habituation in
neuropsychiatric disorders are made more difficult by inconsistent and
problematic methods used to assess and interpret habituation altera-
tions. In this review we have provided suggestions for appropriate re-
search protocols to assess habituation and guidelines for how to de-
scribe different types of habituation abnormalities with the hope that
this will help clarify the field. The fact that habituation has clear sig-
nificance to neuropsychiatry should now catalyze researchers to more
systematically and appropriately assess habituation to determine how it
can be used for diagnosis, treatment, or understanding the mechanisms
underlying neuropsychiatric disorders.
Acknowledgements
TM is supported by a CIHR CGSM. AB is supported by an NSERC
CGSM. CHR is supported by a CIHR (operating grant #CIHR MOP
130287) and an NSERC Discovery grant (NSERC RGPIN 1222216-13).
We would like to thank Dr. Evan Ardiel for comments and suggestions
on the manuscript.
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